Associations between genetically predicted iron status and cardiovascular disease risk: A Mendelian randomization study

Abstract

Background: Mendelian randomization (MR) studies suggest a causal effect of iron (Fe) status on cardiovascular disease (CVD) risk, but it is unknown if these associations are confounded by pleiotropic effects of the instrumental variables (IV) on CVD risk factors. We aimed to investigate the effect of Fe status on CVD risk controlling for CVD risk factors.

Methods: Fe biomarker IVs (total Fe binding capacity (TIBC, n=208,422), transferrin saturation (TSAT, n=198,516), serum Fe (SI, n=236,612), ferritin (n=257,953)) were selected from a European GWAS meta-analysis. We performed two-sample univariate (UV) MR of each Fe trait on CVD outcomes (all-cause ischemic stroke (IS), cardioembolic IS (CES), large artery IS (LAS), small vessel IS (SVS), and coronary heart disease (CHD)) from MEGASTROKE (n=440,328) and CARDIoGRAMplusC4D (n=183,305). We then implemented multivariate (MV) MR conditioning on six CVD risk factors from independent European samples to evaluate their potential confounding and/or mediating effects on the observed Fe-CVD associations.

Results: With UVMR analyses, we found higher genetically predicted Fe status to be associated with a greater risk of CES (TSAT: OR 1.17 [95%CI 1.03, 1.33], SI: OR 1.21 [ 95%CI 1.02, 1.44]; TIBC: OR 0.81 [95%CI 0.69, 0.94]). The detrimental effects of Fe status on CES risk remained unaffected when adjusting for CVD risk factors (all P<0.05). Additionally, we found diastolic blood pressure (DBP) to mediate between 7.1-8.8% of the total effect of Fe status on CES incidence. While UVMR initially suggested a protective effect of Fe status on LAS and CHD, MVMR analyses factoring CVD risk factors revealed a complete annulment of this perceived protective effect (all P>0.05).

Discussion: Higher Fe status was associated with a greater risk of CES independent of CVD risk factors, and this effect was partly mediated by DBP. These findings support a role of Fe status as a modifiable risk factor for CES.

Keywords: Mendelian randomization; cardioembolic stroke risk; iron status; ischemic stroke.

Figure 1.. Study design and workflow.

CVD, cardiovascular disease; Fe, iron; IVW, inverse variance weighted; MR, Mendelian Randomization; MR-PRESSO, Mendelian randomization pleiotropy residual sum and outlier test; MVMR, multivariate mendelian randomization.

Figure 2.. Associations between genetically predicted iron status and cardioembolic ischemic stroke using univariate and multivariate Mendelian randomization.

MR estimates presented as odds ratio (OR) and 95% confidence intervals (CI) per 1-SD unit increase in the Fe exposure. Apo-A, apolipoprotein-A; Apo-B, apolipoprotein-B; BMI, body mass index; CES, cardioembolic ischemic stroke; DBP, diastolic blood pressure; LDL, low density lipoprotein cholesterol; MVMR, multivariate Mendelian randomization; TC, total cholesterol; TG, triglycerides; UVMR, univariate Mendelian randomization.

Figure 3.. Associations between genetically predicted iron status and atherosclerotic cardiovascular disease outcomes using univariate and multivariate Mendelian randomization.

MR estimates presented as odds ratio (OR) and 95% confidence intervals (CI) per 1-SD unit increase in the Fe exposure. Apo-A, apolipoprotein-A; Apo-B, apolipoprotein-B; BMI, body mass index; DBP, diastolic blood pressure; CHD, coronary heart disease; LAS, large artery atherosclerotic ischemic stroke; LDL, low density lipoprotein cholesterol; MVMR, multivariate Mendelian randomization; TC, total cholesterol; TG, triglycerides; UVMR, univariate Mendelian randomization.